Regulation, function and relevance of adult neurogenesis

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Adult neurogenesis is the process of development of new functioning neurons in the adult brain. It has been described for all mammalian species investigated, including non-human primates and humans.

First described in the 1960s by Josef Altman, it attracted widespread interest only from the 1990s onwards, when the link to neural stem cell biology had become apparent. Adult neurogenesis occurs in two neurogenic regions; the dentate gyrus of the hippocampus and the olfactory bulb, originating from precursor cells in the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles. There is evidence suggesting it might also occur outside the two neurogenic regions, either:

in abortive form (i.e. to the level of the expression of immature neuronal markers)

in reaction to damage and ischemia

at very low physiological levels

Nonetheless, the available data are often conflicting and a complete coherent picture has not emerged as of yet.

Neural precursor cells properties

Dentate gyrus and olfactory bulb neural precursor cells display stem cell properties (self-renewal and multipotency) when put into cell culture but usually show a more limited potential in vivo. They reside within a neurogenic niche resembling other stem cell niches in the body, e.g. bone marrow or testes and possess glial features and radial glia properties. They typically express markers such as Nestin or Sox2, but no specific proteins have been found that would allow prospective isolation. Neural precursor cells from the two neurogenic regions show different properties ex vivo but the few available cross-transplantation experiments suggest a major impact of the niche on the actual differentiation potential.​

Regulation of adult neurogenesis

The process of neurogenesis decreases with age but appears to continue at low levels, even at old age. Behavioral stimuli, including physical activity, exposure to complexity, and learning seem to regulate this process, which is also controlled at all different stages of neuronal development (proliferation of precursor cells, survival, migration, maturation and functional synaptic integration). Many genes with relevance for cortical neurogenesis in the embryo are also involved in adult neurogenesis, with notable examples being Pax6, Neurogenin2, Mash1 (Ascl1) and NeuroD1. Molecular details differ between the two neurogenic regions reflecting the different lineages of new neurons: glutamatergic principal neurons (granule cells) in the dentate gyrus and (at least) two types of interneurons in the olfactory bulb. Prox1, for example, is only expressed in the SGZ; Olig2 almost exclusively in the SVZ.

Function in the hippocampus

New neurons in the adult hippocampus might contribute to optimizing the strength of the highly plastic mossy fiber connection between the dentate gyrus and area CA3 and are thus exerting a function at a bottleneck in the hippocampal network. They have also been linked to the processing of information in the sense of forming temporal associations and integrating information into contexts. New hippocampal neurons also play a role in affective behavior, underscoring the link between cognition and emotion.

Function in the adult olfactory bulb

New neurons in the adult olfactory bulb have been linked to the maintenance of network integrity in the face of the high turnover rate of receptor neurons in the olfactory epithelium. They also contribute to the variety of olfactory interneurons, show increased sensitivity to novel odors, including pheromones and might be involved in the formation of olfactory memories.

Medical relevance

Adult neurogenesis in the hippocampus has been brought into connection with the pathogenesis of particular (cognitive aspects of) dementias, major depression and schizophrenia. It might be relevant for explaining cognitive impairment in aging due to decreasing plasticity and may be impaired in the context of various conditions, explaining hippocampus-dependent cognitive symptoms (e.g. as a result of infection or diabetes). Similarly, adult neurogenesis in the olfactory bulb might be impaired in the context of various conditions, explaining symptoms related to olfaction (such as those encountered in Parkinson’s and Alzheimer’s sufferers). It might also provide precursor cells attracted to the site of pathology, e.g. after a stroke in the striatum.